Chronic Critical Illness Elicits a Unique Circulating Leukocyte Transcriptome in Sepsis Survivors

Surgical sepsis has evolved into two major subpopulations: patients who rapidly recover, and those who develop chronic critical illness (CCI). Our primary aim was to determine whether CCI sepsis survivors manifest unique blood leukocyte transcriptomes in late sepsis that differ from transcriptomes among sepsis survivors with rapid recovery. In a prospective cohort study of surgical ICU patients, genome-wide expression analysis was conducted on total leukocytes in human whole blood collected on days 1 and 14 from sepsis survivors who rapidly recovered or developed CCI, defined as ICU length of stay ≥ 14 days with persistent organ dysfunction. Both sepsis patients who developed CCI and those who rapidly recovered exhibited marked changes in genome-wide expression at day 1 which remained abnormal through day 14. Although summary changes in gene expression were similar between CCI patients and subjects who rapidly recovered, CCI patients exhibited differential expression of 185 unique genes compared with rapid recovery patients at day 14 (p < 0.001). The transcriptomic patterns in sepsis survivors reveal an ongoing immune dyscrasia at the level of the blood leukocyte transcriptome, consistent with persistent inflammation and immune suppression. Furthermore, the findings highlight important genes that could compose a prognostic transcriptomic metric or serve as therapeutic targets among sepsis patients that develop CCI.

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Dysregulated Immunity and Immunotherapy after Sepsis

Journal of Clinical Medicine ◽

10.3390/jcm10081742 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1742

Author(s):

Dijoia B. Darden ◽

Lauren S. Kelly ◽

Brittany P. Fenner ◽

Lyle L. Moldawer ◽

Alicia M. Mohr ◽

...

Keyword(s):

Immune System ◽

Critical Illness ◽

The Elderly ◽

Long Term Outcomes ◽

Diagnosis And Management ◽

Persistent Inflammation ◽

Chronic Critical Illness ◽

Initial Hospitalization ◽

Sepsis Survivors

Implementation of protocolized surveillance, diagnosis, and management of septic patients, and of surgical sepsis patients in particular, is shown to result in significantly increased numbers of patients surviving their initial hospitalization. Currently, most surgical sepsis patients will rapidly recover from sepsis; however, many patients will not rapidly recover, but instead will go on to develop chronic critical illness (CCI) and experience dismal long-term outcomes. The elderly and comorbid patient is highly susceptible to death or CCI after sepsis. Here, we review aspects of the Persistent Inflammation, Immunosuppression, and Catabolism Syndrome (PICS) endotype to explain the underlying pathobiology of a dysregulated immune system in sepsis survivors who develop CCI; then, we explore targets for immunomodulatory therapy.

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Chronic Critical Illness and PICS Nutritional Strategies

Journal of Clinical Medicine ◽

10.3390/jcm10112294 ◽

2021 ◽

Vol 10 (11) ◽

pp. 2294

Author(s):

Martin D. Rosenthal ◽

Erin L. Vanzant ◽

Frederick A. Moore

Keyword(s):

Critical Illness ◽

Low Grade ◽

Long Term Outcomes ◽

Persistent Inflammation ◽

Chronic Critical Illness ◽

Similar Phenotype ◽

Sepsis Survivors ◽

Low Grade Inflammation ◽

Nutritional Strategies

The nutritional hallmark of chronic critical illness (CCI) after sepsis is persistent inflammation, immunosuppression, and catabolism syndrome (PICS), which results in global resistance to the anabolic effect of nutritional supplements. This ultimately leaves these patients in a downward phenotypic spiral characterized by cachexia with profound weakness, decreased capacity for rehabilitation, and immunosuppression with the propensity for sepsis recidivism. The persistent catabolism is driven by a pathologic low-grade inflammation with the inability to return to homeostasis and by ongoing increased energy expenditure. Better critical care support systems and advances in technology have led to increased intensive care unit (ICU) survival, but CCI due to PICS with poor long-term outcomes has emerged as a frequent phenotype among ICU sepsis survivors. Unfortunately, therapies to mitigate or reverse PICS-CCI are limited, and recent evidence supports that these patients fail to respond to early ICU evidence-based nutrition protocols. A lack of randomized controlled trials has limited strong recommendations for nutrition adjuncts in these patients. However, based on experience in other conditions characterized by a similar phenotype, immunonutrients aimed at counteracting inflammation, immunosuppression, and catabolism may be important for improving outcomes in PICS-CCI patients. This manuscript intends to review several immunonutrients as adjunctive therapies in treating PICS-CCI.

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Persistent inflammation, immunosuppression and catabolism syndrome: mechanisms of sarcopenia and ways of correction

EMERGENCY MEDICINE ◽

10.22141/2224-0586.16.7-8.2020.223712 ◽

2021 ◽

Vol 16 (7-8) ◽

pp. 110-117

Author(s):

S.M. Chuklin ◽

S.S. Chuklin ◽

G.V. Shershen

Keyword(s):

Intensive Care ◽

Critical Illness ◽

Necrotizing Pancreatitis ◽

Clinical Manifestations ◽

Severe Trauma ◽

Significant Loss ◽

Mild Degree ◽

Persistent Inflammation ◽

Chronic Critical Illness ◽

Severe Pathology

Due to advances in intensive care, many patients with severe pathology are discharged from intensive care units. However, prolonged mild degree inflammation persists in some patients, recovery is protracted, and chronic critical illness develops in them. In addition, persistent inflammation, immunosuppression and catabolism arise. In 2012, this condition was identified as a separate syndrome, which can be observed after severe trauma and burns, sepsis, necrotizing pancreatitis. Significant loss of muscle mass that is difficult to correct is one of the leading clinical manifestations in this case. Using literature from the MEDLINE database, modern ideas about the mechanisms of sarcopenia in the persistent inflammation, immunosuppression and catabolism syndrome and possible ways of optimal anabolic support are described.

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Persistently increased cell-free DNA concentrations only modestly contribute to outcome and host response in sepsis survivors with chronic critical illness

Surgery ◽

10.1016/j.surg.2019.11.018 ◽

2020 ◽

Vol 167 (3) ◽

pp. 646-652 ◽

Cited By ~ 1

Author(s):

Russell B. Hawkins ◽

Julie A. Stortz ◽

David C. Holden ◽

Zhongkai Wang ◽

Steven L. Raymond ◽

...

Keyword(s):

Critical Illness ◽

Host Response ◽

Cell Free Dna ◽

Free Dna ◽

Chronic Critical Illness ◽

Sepsis Survivors

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The critical illness mortality inflection point during prolonged Surgical ICU length of stay

Pulmonary and Critical Care Medicine ◽

10.15761/pccm.1000144 ◽

2018 ◽

Vol 3 (1) ◽

Cited By ~ 2

Author(s):

Niels D. Martin ◽

Tara Ramaswamy ◽

Emily Moin ◽

Joshua A. Marks ◽

Tara Collins ◽

...

Keyword(s):

Critical Illness ◽

Length Of Stay ◽

Inflection Point ◽

Icu Length Of Stay ◽

Surgical Icu

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Biomarker Evidence of the Persistent Inflammation, Immunosuppression and Catabolism Syndrome (PICS) in Chronic Critical Illness (CCI) after Surgical Sepsis

Annals of Surgery ◽

10.1097/sla.0000000000005067 ◽

2021 ◽

Vol Publish Ahead of Print ◽

Author(s):

Dijoia B. Darden ◽

Scott C. Brakenridge ◽

Philip A. Efron ◽

Gabriela L. Ghita ◽

Brittany P. Fenner ◽

...

Keyword(s):

Critical Illness ◽

Persistent Inflammation ◽

Chronic Critical Illness

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22: CIRCULATING LEUKOCYTE TRANSCRIPTOMES IN CHRONIC CRITICAL ILLNESS VS. RAPID RECOVERY SEPSIS PATIENTS

Critical Care Medicine ◽

10.1097/01.ccm.0000618588.59696.bf ◽

2020 ◽

Vol 48 (1) ◽

pp. 11-11

Author(s):

Dijoia Darden ◽

Maria-Cecilia Lopez ◽

Julie Stortz ◽

Russell Hawkins ◽

Michael Cox ◽

...

Keyword(s):

Critical Illness ◽

Rapid Recovery ◽

Chronic Critical Illness

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Consumptive coagulopathy is associated with organ dysfunction during PICS

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00521.2018 ◽

2019 ◽

Vol 316 (5) ◽

pp. L946-L952 ◽

Cited By ~ 5

Author(s):

Leah K. Winer ◽

Nadine Beckmann ◽

Rosalie A. Veile ◽

Michael D. Goodman ◽

Charles C. Caldwell ◽

...

Keyword(s):

Critical Illness ◽

Cecal Ligation ◽

Multiple Organ ◽

Concomitant Increase ◽

Consumptive Coagulopathy ◽

Coagulation Abnormalities ◽

Persistent Inflammation ◽

Chronic Critical Illness ◽

Outbred Mice ◽

Cardinal Feature

Patients who survive the acute phase of sepsis can progress to persistent inflammation, immunosuppression, and catabolism syndrome (PICS). Although sepsis is characterized by early hypercoagulability and delayed hypocoagulability, coagulopathy during chronic critical illness is not fully understood. The objective of this study was to determine whether sepsis-induced PICS is associated with coagulation abnormalities. Using our previously described murine PICS model, outbred mice underwent cecal ligation and puncture, and coagulability was characterized after 8 days. We found that during PICS the spleen became markedly enlarged with increased splenocytes and splenic megakaryocytes without a concomitant increase in circulating platelets. Microscopy revealed a nearly sevenfold increase in pulmonary microvascular thrombi in PICS mice, along with significantly decreased pulmonary tidal volumes and inspiratory times and with significantly increased respiratory rates. Thromboelastometry showed that PICS mice had significantly delayed clot initiation time but increased clot firmness. Finally, PICS mice displayed delayed thrombin production and decreased overall thrombin concentrations. All together, these data demonstrate a general dysregulation of coagulation resulting in microthrombus formation and compromised lung function. On the basis of these findings, we propose that consumptive coagulopathy constitutes another cardinal feature of PICS and may contribute to the ongoing tissue damage and multiple organ failure that can occur in chronic critical illness.

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